Highlights from the Patents pubs.acs.org/OPRD
A Review of U.S. Patents in the Field of Organic Process Development Published During April and May 2012
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SUMMARY The current review contains 21 patents from an original list of 277 that fitted the selection criteria. One patent in particular evoked memories of the stories of horrific birth defects that appeared in the 1950s and 60s due to the drug thalidomide. Derivatives of this compound are under investigation for treating cancers, and a patent describes the synthesis of some of these molecules. There is a wide range of subjects in this selection. Some of the patents contain extensive amounts of experimental information, while others have very little. A feature of several patents is that changing solvents gives marked improvement in selectivity and productivity as well as reducing environmental impact. High cholesterol levels lead to coronary problems and are treated by a number of drugs including a range of statins. A comprehensive patent covers the synthesis of the side chain of several statins and contains a number of novel intermediates. Another drug used to treat the same problem is ezetimibe, and a detailed patent describes its synthesis that includes a previously unpublished finding that a side product, from a Ti(IV)-catalysed Mannich reaction, can be converted into a useful intermediate. A detailed patent describes the synthesis of azobicyclohexane esters that are used to prepare drugs for the treatment of hepatitis C. The route proceeds via novel bisulfite compounds that do not need to be isolated. Carbamoyl leucine derivatives are alternative antiviral drugs for treating hepatitis C, and a patent describes how they can be made with minimum byproducts by careful control of pH. A third patent covers a range of aminohydroxycarboxamides that are intermediates for another class of hepatitis C drugs. The process produces crystals that are easy to filter and avoids the use of solvents such as DMF and dioxane that give solid masses. Another antiviral drug is etravirine that is used in treating HIV, and a new process for its synthesis proceeds via a novel ether compound. The ether is formed along with an isomer that can also be converted to the final product, thus increasing overall yield. A process is described for producing sterile batches of the β-lactam antibiotic meropenem trihydrate. The process is claimed to be commercially viable, but in a catalytic hydrogenation step an almost stoichiometric amount of a Pd catalyst is required. A patent covering the preparation of pyrroles involves the synthesis of γ-nitrodicarbonyl and subsequent oxidation to an γ-dicarbonyl with H2O2. Reducing the amount of H2O in the process gives improved selectivity. Two patents describe methods for preparing aminobenzene compounds by processes that reduce the need for solids handling and, thereby, exposure to compounds that are toxic and skin sensitizers. Another patent on amine compounds covers an aminopyridine that is used to produce the fungicide fluazinam. The process uses the same reagents as an original procedure and gives improved selectivity, yield, and productivity by using MIBK instead of DMF as reaction solvent. Imatinib is used for the treatment of leukaemia and is available as the mesylate, under the name Gleevec. An improved synthetic route for a key intermediate is described that avoids some of the complex workup methods of alternative © 2012 American Chemical Society
routes. An aldehyde that is used as perfume in soaps, shampoos, and cosmetics can contain unacceptably high levels HOAc that is unsuitable in these applications. An improved synthesis of the compound is reported that does require isolation of intermediates and gives a product with very low HOAc levels. The synthesis of the antidepressant mirtazapine involves the use of concd H2SO4 in a cyclisation step. The subsequent product extraction is improved by using PrnOH or PriOH in place of DCM that can leave unacceptable residues. Ziprasidone is an antipsychotic drug used to treat schizophrenia, and it can contain impurities causing discolouration in the final product. Despite a multistep purification procedure using several solvents and filtration steps the yield and the final purity are both very high. A one-pot process is described for the synthesis of rufinamide, an anticonvulsant used with other drugs for the treatment of seizure disorders. The process is carried out in aqueous solution and avoids the need to isolate or purify intermediates. A detailed patent covers the synthesis of novel cyclopropyl carboxylic acid derivatives that are pharmaceutical intermediates. Dihydropteridione derivatives are useful in treating tumours, and a very detailed patent describes the preparation of crystalline salts but uses a large number of solvents. The cis isomer of a azabicycloalkanol derivative is an intermediate in agrochemical synthesis, but the trans isomer is unsuitable. A new process gives improved yield of the cis isomer and provides an isomerisation step to increase the cis/trans ratio. 2,2-Difluoroethylamine is a useful intermediate, and a patent describes an improved synthesis by amination with NH3 that gives high yields when the amount of H2O in the system is minimised. Several of the patents in this collection describe experiments carried out on a kilo or multikilo scale, and this may suggest an advanced stage of development or even commercial operation. However, there is no legal or commercial significance in the choice of patents in this review. The advantages mentioned in this review are those claimed in the patent, unless this reviewer has personal knowledge of the subject.
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PATENT NO. U.S. 8,148,520 Assignee: Orchid Chemicals and Pharmaceuticals Limited, Chennai, India Title or Subject: Process for the Preparation of β-Lactam Antibiotic Meropenem Trihydrate Meropenem 4b, is used to treat a number of infections and is available as the trihydrate as Merrem in the United States. A number of synthetic routes to 4b are mentioned, some of which use chromatographic methods or multiple solvent systems for the preparation of the sterile product. This patent describes a method for the preparation of sterile 4b by crystallisation, and this is the subject of the patent claims. The patent also describes a method for the synthesis of 4b by the route outlined in Scheme 1. This is claimed to be commercially viable and does not require Published: August 24, 2012 1468
dx.doi.org/10.1021/op3002118 | Org. Process Res. Dev. 2012, 16, 1468−1481
Organic Process Research & Development
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Scheme 1a
Highlights from the Patents
PATENT NO. U.S. 8,148,545 Assignee: Chevron Phillips Chemical Company LP, The Woodlands, Texas, United States Title or Subject: Process for the Synthesis of γNitrodicarbonyl and γ-Dicarbonyl Compounds and Their Pyrrole Derivatives The patent covers methods for synthesising the γ-nitrodicarbonyl 9 that is used to prepare the pyrrole 11. This is a component of a catalyst system used in the polymerisation of olefins. The process for preparing 11 is outlined in Scheme 3 and Scheme 3a
a Reagents and conditions: (a) (i) EtNPri2, MeCN, −10 °C; (ii) K2HPO4, EtOAc, rt, 0.25 h; (iii) Pri2O, rt, 1 h; (iv) filter, dry; (b) step a at 15 °C. (c) (i) Pd/C, rt, H2, EtOAc/THF/H2O; (ii) filter, H2O wash, separate, active C; (iv) filter, add THF, filter, dry.
Scheme 2a a Reagents and conditions: (a) K2CO3, H2O, rt, 1 h. (b) (i) 30% H2O2,
